Inhibition of amiloride-sensitive epithelial Na+ absorption by extracellular nucleotides in human normal and cystic fibrosis airways

Mall, M., Wissner, A., Gonska, T., Calenborn, D., Kuehr, J., Brandis, M. and Kunzelmann, K. (2000) Inhibition of amiloride-sensitive epithelial Na+ absorption by extracellular nucleotides in human normal and cystic fibrosis airways. American Journal of Respiratory Cell and Molecular Biology, 23 6: 755-761.


Author Mall, M.
Wissner, A.
Gonska, T.
Calenborn, D.
Kuehr, J.
Brandis, M.
Kunzelmann, K.
Title Inhibition of amiloride-sensitive epithelial Na+ absorption by extracellular nucleotides in human normal and cystic fibrosis airways
Journal name American Journal of Respiratory Cell and Molecular Biology   Check publisher's open access policy
ISSN 1044-1549
Publication date 2000
Sub-type Article (original research)
Volume 23
Issue 6
Start page 755
End page 761
Total pages 7
Place of publication New York, USA
Publisher American Thoracic Society
Collection year 2000
Language eng
Subject C1
270104 Membrane Biology
730110 Respiratory system and diseases (incl. asthma)
1103 Clinical Sciences
Abstract Cystic fibrosis (CF) airway epithelia are characterized by enhanced Na+ absorption probably due to a lack of downregulation of epithelial Na+ channels by mutant CF transmembrane conductance regulator. Extracellular nucleotides adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP) have been shown to activate alternative Ca2+-dependent CI- channels in normal and CF respiratory epithelia, Recent studies suggest additional modulation of Na+ absorption by extracellular nucleotides. In this study we examined the role of mucosal ATP and UTP in regulating Na+ transport in native human upper airway tissues from patients with 16 patients with CF and 32 non-CF control subjects. To that end, transepithelial voltage and equivalent short-circuit current (I-sc) were assessed by means of a perfused micro-Ussing chamber. Mucosal ATP and UTP caused an initial increase in lumen-negative I-sc that was followed by a sustained decrease of I-sc in both non-CF and CF tissues. The amiloride-sensitive portion of I-sc was inhibited significantly in normal and CF tissues in the presence of either ATP or UTP, Both basal Na+ transport and nucleotide-dependent inhibition of amiloride-sensitive I-sc were significantly enhanced in CF airways compared with non-CF, Nucleotide-mediated inhibition of Na+ absorption was attenuated by pretreatment with the Ca2+-adenosine triphosphatase inhibitor cyclopiazonic acid but not by inhibition of protein kinase C with bisindolylmaleimide, These data demonstrate sustained inhibition of Nat transport in non-CF and CF airways by mucosal ATP and UTP and suggest that this effect is mediated by an increase of intracellular Ca2+. Because ATP and UTP inhibit Na+ absorption and stimulate CI- secretion simultaneously, extracellular nucleotides could have a dual therapeutic effect, counteracting the ion transport defect in CF lung disease.
Keyword Biochemistry & Molecular Biology
Cell Biology
Respiratory System
Transmembrane Conductance Regulator
Cl Secretion
Respiratory Epithelia
Mediated Inhibition
Xenopus Oocytes
Phospholipase-c
Nasal Epithelia
Ion-transport
Wild-type
Cells
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Tue, 10 Jun 2008, 11:33:25 EST